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Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial

Joao Pedro Ferreira 1, 2, 3, 4, 5 Kévin Duarte 1, 2, 3, 4, 5 Holger Woehrle 6 Martin Cowie 7 Christiane Angermann 8 Marie-Pia D’ortho 9, 10 Erland Erdmann 11 Patrick Levy 12 Anita Simonds 13 Virend Somers 14 Helmut Teschler 15 Karl Wegscheider 16 Emmanuel Bresso 17 Marie Dominique-Devignes 17 Patrick Rossignol 1, 2, 3, 4, 5 Wolfgang Koenig 18 Faiez Zannad 1, 2, 3, 4, 5 
Abstract : INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.
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Submitted on : Friday, March 20, 2020 - 6:38:53 PM
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Joao Pedro Ferreira, Kévin Duarte, Holger Woehrle, Martin Cowie, Christiane Angermann, et al.. Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial. Clinical Research in Cardiology, Springer Verlag, 2019, 109 (7), pp.881-891. ⟨10.1007/s00392-019-01578-9⟩. ⟨hal-02513627⟩



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